Genetically modified rat models for severe combined immunodeficiency (scid)

Abstract

This invention relates to the engineering of animal cells, preferably mammalian, more preferably rat, that are deficient due to the disruption of tumor suppressor gene(s) or gene product(s). In another aspect, the invention relates to genetically modified rats, as well as the descendants and ancestors of such animals, which are animal models of human cancer and methods of their use.

1 .- 53 . (canceled) 
     
     
         54 . A genetically modified non-human mammal, or progenies thereof, at least some of whose cells comprise a genome comprising a genetic mutation in one or more genes that causes the mammal to have a greater susceptibility to Severe Combined Immunodeficiency (SCID) than a mammal not comprising the genetic mutation. 
     
     
         55 . The mammal of  claim 54 , wherein said gene is selected from the group consisting of Ada, Rag1, Rag2, Dclre1c, Nhej1, Jak3, Il7r, Ptprc, Cd3d, Cd3e, Il2rg, Prkdc, Sirpa, Foxn1, genes having at least about 80% sequence identity to a gene selected from Ada, Rag1, Rag2, Dclre1c, Nhej1, Jak3, Il7r, Ptprc, Cd3d, Cd3e, Il2rg, Prkdc, Sirpa, Foxn1, and combinations thereof. 
     
     
         56 . The genetically modified nonhuman mammal of  claim 54 , wherein the mammal is a rat. 
     
     
         57 . The genetically modified nonhuman mammal of  claim 54 , wherein one or more SCID genes or loci are misexpressed and/or conditionally misexpressed. 
     
     
         58 . The non-human animal model of  claim 54 , wherein the genetic mutation results in decreased expression of one or more SCID proteins. 
     
     
         59 . The genetically modified nonhuman mammal of  claim 54 , wherein the one or more genes encoding a SCID protein is disrupted. 
     
     
         60 . The genetically modified nonhuman mammal of  claim 54 , wherein the SCID gene is selected from the group consisting of Ada, Rag1, Rag2, Jak3, and Prkdc. 
     
     
         61 . The genetically modified nonhuman mammal of  claim 57 , wherein the cells are pluripotent cells. 
     
     
         62 . The genetically modified nonhuman mammal of  claim 54 , wherein the one or more SCID genes or loci are disrupted by a mechanism selected from mutating directly in the germ cells of a living organism; removal of DNA encoding all or part of the SCID protein; insertion mutation; transposon insertion mutation; deletion mutation; introduction of a cassette or gene trap by recombination; chemical mutagenesis; RNA interference (RNAi); mutagenesis by site-specific nuclease; or delivery of a transgene encoding a dominant negative protein, which may alter the expression of a target gene. 
     
     
         63 . The genetically modified nonhuman mammal of  claim 54 , wherein the one or more SCID genes or loci are disrupted by a transposon insertion mutation. 
     
     
         64 . The genetically modified nonhuman mammal of  claim 61 , wherein the disruption causes a complete or partial loss-of-function phenotype. 
     
     
         65 . The genetically modified nonhuman mammal of  claim 54 , wherein said gene is capable of being regulated via transcriptional control. 
     
     
         66 . The genetically modified nonhuman mammal of  claim 54 , wherein said genetic mutation is conditionally complemented by conditional expression of a transgene. 
     
     
         67 . A screening method for identifying useful compounds, comprising (a); contacting a rat model system comprising a genetically modified nonhuman mammal of  claim 54 , or progenies thereof, at least some of whose cells comprise a genome comprising a genetic mutation in one or more SCID genes that causes the mammal to have a greater susceptibility to Severe Combined Immunodeficiency (SCID) induction than a mammal not comprising the genetic mutationwith a candidate test agent; and (b) detecting a phenotypic change in the model system that indicates that the SCID function is restored when compared relative to wild-type cells. 
     
     
         68 . The screening method of  claim 67 , wherein the method is used for identifying useful compounds for the treatment of a disease or condition selected from the group consisting of hyperproliferative disorders, transplantation conditions, stem cell disorders, and immunological disorders.